Process for the manufacture of Δ16 -steroid-14β,18,20-triols and -14β,20-diol-18-ols of the pregnane series

ABSTRACT

The invention is for a selective reduction of the 20- oxo group in Δ 16  -steroid-14β,18-diol-20-ones of the pregnane series to form the two epimeric 20-alcohols having the 20 S and 20 R configuration. The process is especially intended for the manufacture of alkaloids of the batrachotoxin type, particularly for batrachotoxinine A, which is a pregnane derivative having a 20 S alcohol grouping, and epimers and derivatives, such as epi-batrachotixinine A or 7,8-dihydrobatrachotoxinine A. The process is characterized by reducing the said Δ 16  -steroid-14β,18-diol-20-ones in form of their 14,18-ketals, for instance the 14,18 acetonides and using appropriate complex light metal hydrides and operating at appropriate temperatures. The separation of the two isomers is easy and can be effected by the usual physical operations, such as crystallization or chromatography. In the 14β,18,20-triols obtained the 18-hydroxy group can be dehydrogenated to the corresponding 18-aldehydes, which are intermediates necessary in the synthesis of the said pharmacological interesting substances, such as batrachotoxin, by treatment with a sulphoxide in the presence of a carboxylic acid anhydride.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation in part of application Ser. No. 364,466 filed onMay 29, 1973 now abandoned which is a continuation in part ofapplication Ser. No. 82 183 filed on Oct. 19, 1970.

The present invention relates to a process for the manufacture of Δ¹⁶-steroid-14β,18,20-triols and Δ¹⁶ -steroid-14β,20-diol-18-als of thepregnane series and their esters and ethers, of which the 17-pregnaneside chain has one of the two following partial formulae ##EQU1##WHEREIN R represents a free, esterified or etherified hydroxyl group,from Δ¹⁶ -steroid-14β,18-diol-20-ones of the pregnane series in whichthe 14,18-diol group is ketalised with a ketone.

The process can serve for the synthesis of pregnane derivatives whichpossess the abovementioned side chain in the 17-position and whichpossess pharmacologically interesting actions, and amongst these thereare especially to be included the alkaloids of the batrachotoxin andbatrachotoxinin A group.

Amongst the pregnane derivatives according to the present inventionwhich have been mentioned, there are to be understood both compounds ofthe 5α- and 5β-pregnane series and their derivatives which have a doublebond starting from the 5-position.

Products of the process which are to be singled out particularly arethose of the following formula ##SPC1##

In which P has one of the abovementioned partial formulae I or II, R₁denotes a free or protected oxo group or a free, esterified oretherified hydroxyl group together with a hydrogen atom, R₂ denotes twohydrogen atoms or a hydrogen atom next to a 7,8-double bond, a protectedoxo group or a hydrogen atom together with a free, esterified oretherified hydroxyl group, R₃ denotes two hydrogen atoms or a hydrogenatom next to a 9,11-double bond or a free or protected oxo group or afree, esterified or etherified hydroxyl group together with a hydrogenatom, R₄ denotes a hydrogen atom or a free, esterified or etherifiedhydroxyl group and R₁ together with R₄ denotes a 3-hydroxy-3,9-oxidogroup or a 3-hydroxy-3,9-oxido group having the 3-hydroxy group inetherified or esterified form, and Z₁ and Z₂ each represent a free,esterified or etherified hydroxyl group and Z₁ and Z₂ together representa ketalised 14,18-diol group and Z₁, however, also represents an oxogroup, and in which double bonds can be present in one of positions 4,5or 5,6 and/or in the case that R₂ or R₃ denotes a hydrogen atom, also inone of positions 7,8 and/or 9,11.

The esterified hydroxyl groups mentioned are preferably derived fromorganic carboxylic acids of the aliphatic, alicyclic, aromatic orheterocyclic series, especially from those with 1-18 carbon atoms, forexample from lower aliphatic carboxylic acids with 1-6 C atoms, forexample from formic acid, acetic acid, propionic acid, the butyricacids, valeric acids, such as n-valeric acid or trimethylacetic acid,trifluoroacetic acid, the caproic acids, such as β-trimethyl-propionicacid or diethylacetic acid or the oenanthic, caprylic, pelargonic orcapric acids, undecylic acid, for example undecylenic acid, lauric,myristic, palmitic or stearic acids, for example oleic acid,cyclopropane-, -butane-, -pentane- and -hexane-carboxylic acid,cyclopropylmethanecarboxylic acid, cyclobutylmethanecarboxylic acid,cyclopentylethanecarboxylic acid, cyclohexylethanecarboxylic acid,cyclopentyl-, cyclohexyl- or phenyl-acetic acid or -propionic acids,benzoic acid, phenoxyalkanoic acids, such as phenoxyacetic acid,dicarboxylic acids, such as succinic acids, phthalic acid, quinolinicacid, furane-2-carboxylic acid, 6-tert.-butyl-furane-2-carboxylic acid,5-bromo-furane-2-carboxylic acid, nicotinic acid or isonicotinic acid,or from pyrrolecarboxylic acids and alkyl-substituted pyrrolecarboxylicacids, such as 2,4,5-trimethylpyrrole-3-carboxylic acid,2,4-dimethyl-pyrrole-3-carboxylic acid or2-ethyl-4-methyl-pyrrole-3-carboxylic acid, or from sulphonic acids,such as benzenesulphonic acids or from inorganic acids such as, forexample, phosphoric acids or sulphuric acids.

Etherified hydroxyl groups are preferably especially those which arederived from alcohols with 1-8 carbon atoms, such as lower aliphaticalkanols with 1-5 C atoms, such as ethyl alcohol, methyl alcohol, propylalcohol, iso-propyl alcohol, butyl alcohols or amyl alcohols or fromaraliphatic alcohols, especially monocyclic aryl-lower aliphaticalcohols, such as benzyl alcohol, or from heterocyclic alcohols, such asα-tetrahydropyranol or α-tetrahydrofuranol.

The ether groups, and especially an etherified hydroxyl group in the14-position can preferably also be derived from sulphur-containingalcohols, for example those of the formulae ##EQU2## wherein V₁ - V₅denote hydrogen or alkyl or aryl groups, especially lower alkyl groups,and φ denotes an aryl group, especially an unsubstituted or substitutedphenyl nucleus, that is to say from 2-thiapropanols or2-thia-arylethanols which are optionally substituted in the 1- and/or3-position by further alkyl or aryl groups, above all from2-thiapropanol. Such ether groups are formed, for example, on treatingthe hydroxy-steroid with dialkyl-sulphoxides or ar-alkyl-sulphoxides ofthe formula ##EQU3## in the presence of a carboxylic acid anhydride,preferably of a lower aliphatic carboxylic acid anhydride.

Examples of protected oxo radicals are ketal groups, preferably thosewhich are derived from lower alkanediols or alkanols, for example fromethylene glycol, methanol or ethanol.

A protected oxo group in the 3-position can in particular also be in theform of the 3-hydroxy-3,9-oxidohemiketal group or the form of the3-ethers or 3-esters of such a hemiketal group, the ethers and estersbeing derived, for example, from the abovementioned alcohols or acids,preferably from lower aliphatic alcohols or acids. In particular, thishemiketal group is a 3α,9α-epoxy-3β-hydroxy group or its 3-ethers or3-esters.

The compounds of the above formula III are valuable intermediateproducts in the manufacture of the pregnane compounds described, forexample, in German Offenlegungsschriften No. 2,029,169, 2,052,166 and2,136,635. Within the group of compounds encompassed by the formula III,compounds of the following formula are of great significance asimportant intermediate products for the manufacture of batrachotoxininA, epibatrachotoxinin A and their 7,8-dihydro derivatives, as well asesters or ethers thereof, especially the 20-pyrrole carboxylic acidesters, which also include the known strongly active alkaloidbatrachotoxin: ##SPC2##

wherein P has the meaning indicated for the formula III, A denotes ahydroxyl group together with a hydrogen atom, or an oxo group, X denotesan etherified or esterified hydroxyl group, Y an esterified hydroxylgroup, and Z denotes a hydrogen atom or an esterified hydroxyl group, aswell as their esters and ethers and ketals of the 14,18-diols. The estergroups, amongst which there are especially also to be understood anesterified group R in the side chain P, are preferably in turn thosefrom the abovementioned carboxylic acids or inorganic acids or sulphonicacids, especially the lower aliphatic carboxylic acids, above all aceticacid. The esterified hydroxyl groups are preferably derived from loweraliphatic alcohols with 1-5 C atoms or from one of the abovementionedheterocyclic alcohols, and especially also from the sulphur-containingalcohols mentioned, preferably from a 2-thiapropanol of the formula C)having up to 8 C atoms, such as, for example, 2-thiapropanol. The14,18-ketals of 14,18-diols are above all those which are derived from aketone of the formula ##EQU4## wherein W₁ and W₂ denote twounsubstituted or substituted hydrocarbon radicals or denote, togetherwith the carbon atom to which they are bonded, an unsubstituted orsubstituted cyclised hydrocarbon radical. These groups W₁ and W₂ areabove all aliphatic or araliphatic hydrocarbon radicals but can also bealicyclic or aromatic; they can optionally also be substituted, forexample by hydroxyl, lower alkoxy, lower acyloxy, thiol or amino groupsor halogen atoms, the term lower alkyl denoting groups with 1-6 carbonatoms. W₁ and W₂, together with the carbon atom to which they arebonded, can also form a cyclised hydrocarbon radical. Such a hydrocarbonradical is preferably an alicyclic hydrocarbon radical with a total of1-12 C atoms and 5-7 ring carbon atoms, above all a cyclopentylidene orcyclohexylidene radical. If the groups W₁ and W₂ individually arehydrocarbon radicals of aliphatic nature, they preferably each possess1-6 carbon atoms and are above all methyl, ethyl, propyl, butyl, pentylor hexyl groups, but can also be of alicyclic nature such as, forexample, cyclopentyl radicals or especially cyclohexyl radicals.Aromatic radicals W₁ and W₂ are in particular phenyl groups or phenylgroups substituted by lower alkyl radicals or halogen atoms.

Araliphatic groups W₁ and/or W₂ are especially those having the saidalkyl groups of 1-6 C atoms and aromatic moiety are phenyl groups or thesaid substituted phenyl groups. Above all, W₁ and W₂ each represents amethyl group, that is to say the 14,18-diols which can be manufacturedaccording to the present process are in the form of acetonides.

Amongst the compounds according to the above formula IV, an outstandingposition is occupied by the compounds of the formulae ##SPC3##

wherein Alk represents a lower alkyl group with 1-6 C atoms, Acrepresents a lower aliphatic acyl radical with 1-6 C atoms and P'represents one of the two partial formulae ##EQU5## wherein R" denoteshydrogen or a lower aliphatic acyl group with 1-6 C atoms, as well asthe derivatives formed by ketalisation of the 14,18-diol grouping of theformula VI with the abovementioned preferred ketones of the formula V,and 14-ethers of the compounds of the formula VII, especially derivedfrom one of the abovementioned alcohols, for example with one of the2-thiapropanols, which have been mentioned, with 2-8 C atoms above all2-thiapropanol. These compounds are particularly valuable for thesynthesis of batrachotoxinin A and epi-batrachotoxinin A and their20-esters, such as batrachotoxin. Specific compounds of this group are,for example, those of the formulae VI and VII wherein Alk denotes methyland Ac denotes acetyl and R" in the formulae VIII or IX denotes hydrogenor acetyl, the 14,18-acetonides in the case of the compounds of theformula VI, and the 14-(2'-thiapropyl)-ethers of the compounds of theformula VII.

The process of the present application for the manufacture of the Δ¹⁶-steroid-14β,18,20-triols and Δ¹⁶ -steroid-14β,20-diol-18-als of thepregnane series and their esters and ethers is characterised in that aΔ¹⁶ -20-oxo-steroid-14β,18-diol of the pregnane series, in which the14,18-diol group is ketalised with a ketone, is treated with a complexlight metal hydride which reduces an oxo group to the hydroxyl group,but which leaves esterified hydroxyl groups intact, and, if desired, inoptional sequence and optionally simultaneously, at least one of the twoepimers is isolated in a manner which is in itself known from themixture of the 20 S and 20 R hydroxy compounds formed, or theirfunctional derivatives, and/or protected functional groups which may bepresent are liberated and/or functional groups are functionally modifiedand/or the 18-hydroxyl group is selectively dehydrogenated to the 18-oxogroup.

The reduction, according to the process, of the starting substanceswhich have been characterised is carried out with complex hydrides whichleave esterified hydroxyl groups intact. As such it is possible to use,above all, alkali metal borohydrides, especially sodium borohydride, andcomplex alkali metal-aluminium hydrides of the type ##EQU6## wherein X₁,X₂ and X₃ each denote a tertiary lower alkyl group and Me denotes analkali metal, such as, for example, tri-tert. butoxy-lithium-aluminiumhydride or tri-tert. amyloxy-lithium-aluminium hydride. The reductionwith these complex hydrides is carried out in a manner which is initself known. The solvents used are, for example, in the case of thecomplex alkali metal -aluminium hydrides mentioned, an ether, such asdiethyl ether, diisopropyl ether, dioxane or tetrahydrofurane, and inthe case of an alkali metal borohydride preferably an aliphatic orcycloaliphatic alcohol such as, for example, methanol, ethanol, propylalcohol, isopropyl alcohol, the butanols or amyl alcohols.

The temperature for carrying out the reduction according to the processcan vary within the wide limits, the ratio of the two 20-epimericalcohols formed in the reaction mixture varying depending on thetemperature chosen. It is possible, especially in the case that alkalimetal borohydrides are used, to work at low temperatures, for example 0°to -50°, but also below, or especially in the case that tri-tert.alkoxy-lithium-aluminium hydrides are used, to work above 0°, forexample between 0° and 100°. The reaction time to be chosen depends onthe starting product used, on the reducing agent and on the reactiontemperature; in general it is several hours.

The isolation of at least one of the epimeric 20-hydroxy compounds fromthe reaction mixture can be carried out before or after the liberationof functional groups, especially of the 14,18-ketal grouping present inthe reduction product, and before or after functional conversion ofother groups, such as especially the 20-alcohol group. The isolation canbe achieved in a manner which is in itself known, by crystallisation,chromatography or other physical or chemical methods.

If desired it is possible, in optional sequence, to convert protectedfunctional groups, such as, for example, ketal, ether or ester groups,into the corresponding free functional groups, and this can be done in amanner which is in itself known. Thus, for example, ketalised oxo groupsor the ketalised 14,18-diol group and ether groups are preferably splitby the action of acid agents such as mineral acids, for examplehydrochloric acid, sulphuric acid or perchloric acid, or organiccarboxylic acids and sulphonic acids such as, for example, loweraliphatic carboxylic acids, for example acetic acid, whilst ester groupsare preferably split by the action of basic agents. Thus, for example,the 14,18-ketal grouping is preferably saponified to the 14,18-diolgroup by the action of a strong acid such as p-toluenesulphonic acid.

The functional modification of hydroxyl groups or oxo groups can also becarried out in a manner which is in itself known. The esterification offree hydroxyl groups can be achieved, for example, by treatment with anacylating derivative of an acid, such as of a carboxylic acid,preferably the anhydride or a halide, for example in the presence of atertiary base, such as pyridine or collidine.

The etherification of free hydroxyl groups is carried out, for example,by treatment with a reactive functional derivative of the alcohol inquestion, such as an alkyl halide or alkyl sulphate, for example adialkyl sulphate, in the presence of an organic or inorganic base suchas sodium hydroxide or potassium hydroxide or pyridine.

The isolation of the 20 R- and 20 S-hydroxy compounds is preferablycarried out on the mixture of the free alcohols obtained directly byreduction with the complex light metal hydride. However, if desired theisolation can be carried out at a later stage, for example afteresterification of free hydroxyl groups, especially of the 20-hydroxylgroup itself, that is to say the epimeric 20-hydroxy compounds can alsobe isolated in the form of one of their functional derivatives.

If compounds with a free 14,18-diol group or with an 18-aldehyde groupare to be manufactured, the 14,18-ketal group is removed at any desiredstage in a manner which is in itself known, for example as describedabove. Preferably, this is done after separating the epimer mixture ofthe 20-alcohols and, especially if the 18-hydroxyl group is subsequentlyto be dehydrogenated to the oxo group, after esterification ofoxidisable free hydroxyl groups, for example of the 20-hydroxyl group.

The selective dehydrogenation of the 18-hydroxyl group to the oxo group,which can optionally be carried out according to the present process, ispreferably carried out after prior protection of oxidisable freehydroxyl groups in other positions, for example after acylation of a20-hydroxyl group. The oxidising agents used are those known from theliterature for the dehydrogenation of a primary alcohol to the aldehydegroup, such as, for example, compounds of hexavalent chromium, forexample chromium trioxide, especially chromium trioxide in pyridine,optionally with the addition of other solvents, such as chlorinatedhydrocarbons, for example methylene chloride, or chromium trioxide inacetone and sulphuric acid (Jones reagent) or chromium trioxide andpyridine-sulphur trioxide complex. A particularly advantageous methodwhich gives good yields is the oxidation with dimethylsulphoxide-aceticanhydride according to the method of Albright and Goldmann (Journal ofthe American Chemical Society 89, 2416 (1967)). It is also possible touse similar mixtures of a homologue of dimethylsulphoxide, such as thosementioned above, of the formulae C) and D), and of acetic anhydride,such as diethylsulphoxide and propionic anhydride. When using thismethod, the 18-hydroxyl group is dehydrogenated to the aldehyde groupand simultaneously the 14-hydroxyl group is etherified with thethiapropanol of the above general formulae A) or B) corresponding to thedialkylsulphoxide in question. When using dimethylsulphoxide, forexample, the 14-hydroxyl group is converted into the 2-thiapropoxy group(or methyl-thio-methoxy group) --O -- CH₂ -- S -- CH₃. The 14-hydroxylgroup etherified in this way can easily be hydrolysed, even under mildconditions, to the alcohol by acid treatment or by treatment withchloramine in dioxanewater. If the acid treatment is carried out, forexample, with hydrochloric acid in an alcohol, the corresponding acetalof the 18-aldehyde group is formed simultaneously.

The 14-ethers, which have been mentioned, of the 18-aldehydes formed areparticularly valuable starting products or intermediate products for themanufacture of batrachotoxinin A and epi-batrachotoxinin A compounds andof their analogues and conversion products, as is shown later.

The 14,18-ketals of Δ¹⁶ -20-oxo-steroid-14β,18-diols of the pregnaneseries, which are to be used as starting substances, can be manufacturedin a manner which is in itself known by reaction of the corresponding14β,18-diols with the desired ketone or, even more advantageously, witha ketal of such a ketone, with addition of an acid agent, preferably incatalytic amounts. The ketals used are preferably lower aliphatic ketalsof the ketone, above all the dimethylketals, for example2,2-dimethoxypropane in the case of acetone, and the reaction ispreferably carried out at room temperature, in the presence of traces ofan acid, for example p-toluenesulphonic acid.

The Δ¹⁶ -20-oxo-steroid-14β,18-diols of the pregnane series which havebeen mentioned are known or can be manufactured according to publishedmethods. In particular, those starting substances are used which possessthe substituents specified above or correspond to the abovementionedformulae III - VII of the process products. The manufacture of suchstarting substances is described, for example, in GermanOffenlegungsschrift No. 2,136,635.

A preferred combination of the process steps described is that after thereduction of the 14,18-ketals of the Δ¹⁶ -20-oxo-steroid-14β,18-diolswith the complex light metal hydrides mentioned, the 20-hydroxyl groupis acylated, in the manner described above, in the corresponding Δ¹⁶-20-hydroxy compounds obtaind, the 14,18-ketal group in the resultingcompounds is split by the action of an acid under mild conditions, asexplained above, and the 18-hydroxyl group is dehydrogenated accordingto the abovementioned method of Albright and Goldmann, using a loweraliphatic dialkylsulphide in the presence of a lower aliphaticcarboxylic acid anhydride, whereby the Δ¹⁶-20-acyloxy-14β-(2'-thialkoxy)-18-als are formed, and, if desired, atleast one of the epimeric 20 R-OH or R-O-Ac and 20 S-OH or S-O-Accompounds formed is isolated at any desired stage. Preferably, theisolation of the compounds which are epimeric in the 20-position iscarried out immediately after the reduction stage, on the free alcohols.This combination is illustrated by the following reaction scheme in thecase of a starting compound corresponding to the compounds of the aboveformula VI ##SPC4##

In this scheme, Alk denotes a lower alkyl group, above all methyl, andAc denotes a lower aliphatic acyl radical, above all acetyl, whilst W₁and W₂ have the meaning indicated for the above formula V. The splittingof the ketal group is carried out under mild conditions, for example bymeans of catalytic amounts of an acid at room temperature and using ashort reaction time; under these conditions, an etherified hemiketalgroup, such as the etherified 3α,9α-hemiketal group shown above, remainsunattacked.

In the above scheme, the reduction is carried out with NaBH₄ at a lowtemperature in methanol, whereupon the 20 S-OH-epimer is formedpredominantly, and this can, without difficulties, be isolated from thereaction product, for example by simple crystallisation. According tothe special combination of process steps described above it is possible,by varying the reaction conditions and the reducing agents, to obtainmixtures of the two epimeric 20-pregnane-alcohols in varying ratios, andthe pure epimers are optionally isolated at any desired stage. Whenusing, for example, the abovementioned hydrides of the formula X at anelevated temperature, for example at 70°, the 20 R-alcohol ispredominantly obtained and this can also be isolated easily from thereaction product.

The conversion of the products of the process into the initiallymentioned pharmacologically active compounds can be illustrated by meansof the following reaction scheme, which shows the conversion of acompound of the above

formula XV into batrachotoxinin A: ##SPC5##

Analogously, 20 S-and 20 R-epimers of, for example, the compoundsdescribed in the abovementioned German Offenlegungsschrift 2,052,166 canbe prepared from corresponding process products of the presentinvention.

The invention is described in the examples which follow. The opticalrotations are measured in chloroform (temperature 22°C), the IR spectraldata are given as wave numbers (cm⁻ ¹), the measurement again beingcarried out in chloroform, and the UV-spectral data relate to themeasurement in ethanol, the figures indicated in each case showing thewavelength λ_(max), expressed in nanometres, and extinction values ε,corresponding to the maximum absorption.

Unless expressly noted otherwise, "working-up" of a reaction mixtureobtained denotes taking up the reaction mixture in ethyl acetate,washing the mixture with water or saturated sodium chloride solutionuntil it is neutral, drying over magnesium sulphate and evaporating in arotary evaporator. Unless otherwise noted, chromatography involves theuse of highest purity silica gel, 0.05-0.2 mm, from Merck, and"crystallisation" or "crystallising" means dissolving in, and separatingout from, acetone-hexane or ether-hexane.

EXAMPLE 1

2 g of 3β-methoxy-3α,9α-oxido-11α-acetoxy-14β,18-dihydroxy-20-oxo-Δ¹⁶-5β-pregnene and 60 mg of p-toluenesulphonic acid in 80 ml of2,2-dimethoxypropane are stirred for 20 minutes. The mixture is thenneutralised with aqueous sodium bicarbonate solution and worked-up. Asingle crystallisation of the crude product, and chromatography of themother liquor, resulting therefrom, in benzene-ethyl acetate (1:1)solution, yields a total of 1.9 g of the (14β → 18)-acetonide of3β-methoxy-3α,9α-oxido-11α-acetoxy-14β,18-dihydroxy-20-oxo-Δ¹⁶-5β-pregnene, melting point 183°-184°C. [α]_(D) = - 47° (0.38). IR:1,730, 1,665, 1,615, 1,370 (strong) and 1,240. UV 239 (8,300 ).

EXAMPLE 2

316 mg of the (14 → 18)-acetonide of3β-methoxy-3α,9α-oxido-11α-acetoxy-14β,18-dihydroxy-20-oxo-Δ¹⁶-5β-pregnene in 15 ml of absolute dioxane are reduced with 700 mg oftritert.butoxy-lithium-aluminium hydride for 15 minutes at 70°C.Customary working-up, and chromatography in methylene chloride-methanol(20:1) mixture, first yield 142 mg of crystalline (14 → 18)-acetonide of(20R)-3β-methoxy-3α,9α-oxido-11α-acetoxy-14β,18,20-trihydroxy-Δ¹⁶-5β-pregnene. Melting point, after three crystallisations, 141°-143°C.IR: 3,500 (broad), 2,830, 1,740 and 1,250.

Later fractions yield 64 mg of amorphous (14 → 18)-acetonide of(20S)-3β-methoxy-3α,9α-oxido-11α-acetoxy-14β,18,20-trihydroxy-Δ¹⁶-5β-pregnene. IR: 3,600, 3,500 (broad), 2,830, 1,738 and 1,240.

EXAMPLE 3

400 mg of the (14 → 18)-acetonide of3β-methoxy-3α,9α-oxido-11α-acetoxy-14β,18-dihydroxy-20-oxo-Δ¹⁶-5β-pregnene are reduced, in 30 ml of absolute dioxane, with 1.2 g oftri-tert.amyloxy-lithium-aluminium hydride for 20 minutes at 80°C.Working-up, and chromatography in methylene chloride-methanol (50:1)solution yield 213 mg of the (14 → 18)-acetonide of(20R)-3β-methoxy-3α,9α-oxido-11α-acetoxy-14β,18,20-trihydroxy-Δ¹⁶-5β-pregnene and 77 mg of the (14 → 18)-acetonide of(20S)-3β-methoxy-3α,9α-oxido-11α-acetoxy-14β,18,20-trihydroxy-Δ¹⁶-5β-pregnene.

EXAMPLE 4

700 mg of the (14 → 18)-acetonide of3β-methoxy-3α,9α-oxido-11α-acetoxy-14β,18-dihydroxy-20-oxo-Δ¹⁶-5β-pregnene, dissolved in 50 ml of absolute methanol, are cooled to-30°C and 500 mg of solid sodium borohydride are added. The mixture isthen stirred for 19 minutes at -30°C and is worked-up andchromatographed in methylene chloride-methanol (50:1) solution. Herein,121 mg of the (14 → 18)-acetonide of(20R)-3β-methoxy-3α,9α-oxido-11α-acetoxy-14β, 18,20-trihydroxy-Δ¹⁶-5β-pregnene are eluted first. Later fractions yield 462 mg of thecorresponding (20S)-epimer.

EXAMPLE 5

331 mg of the (14 → 18)-acetonide of(20R)-3β-methoxy-3α,9α-oxido-11α-acetoxy-14β,18,20-trihydroxy-Δ¹⁶-5β-pregnene are acetylated in 40 ml of acetic anhydridepyridine (1:1)mixture overnight at room temperature. The reaction mixture is thenevaporated in vacuo and the crude product, in methylene chloride, isfiltered over neutral aluminium oxide (activity III). This yields 320 mgof amorphous (14 → 18)-acetonide of(20R)-3β-methoxy-3α,9α-oxido-11α,20-diacetoxy-14.beta.,18-dihydroxy-Δ¹⁶-5β-pregnene. IR: 1,730 and 1,240.

EXAMPLE 6

495 mg of the (14 → 18)-acetonide of(20S)-3β-methoxy-3α,9α-oxido-11α-acetoxy-14β,18,20-trihydroxy-Δ¹⁶-5β-pregnene are acetylated as in the preceding example. This yields 501mg of amorphous (14 → 18)-acetonide of(20S)-3β-methoxy-3α,9α-oxido-11β,20-diacetoxy-14.beta.,18-dihydroxy-Δ¹⁶-5β-pregnene. IR: 1,730 and 1,240.

EXAMPLE 7

330 mg of the (14 → 18)-acetonide of(20R)-3β-methoxy-3α,9α-oxido-11α,20-diacetoxy-14.beta.,18-dihydroxy-Δ¹⁶-5β-pregnene are dissolved in 40 ml of methanol and a solution of 40 mgof p-toluenesulphonic acid in a mixture of 20 ml of methanol and 4 ml ofwater is added. The reaction mixture is then left to stand at roomtemperature for 3/4 hours and is subsequently worked-up. This yields 280mg of(20R)-3β-methoxy-3α,9α-oxido-11α,20-diacetoxy-14.beta.,18-dihydroxy-Δ¹⁶-5β-pregnene, which are not purified. IR: 3,550 (broad), 3,400 (broad),1,730 and 1,250.

EXAMPLE 8

530 mg of the (14 → 18)-acetonide of(20S)-3β-methoxy-3α,9α-oxido-11α,20-diacetoxy-14.beta.,18-dihydroxy-Δ¹⁶-5β-pregnene, in 35 ml of absolute methanol, are left to stand with 15mg of p-toluenesulphonic acid for 15 minutes at room temperature.Working-up, and one crystallisation of the crude product from methylenechloride-hexane, yield 398 mg of crystals of(20S)-3β-methoxy-3α,9α-oxido-11α,20-diacetoxy-14.beta.,18-dihydroxy-Δ¹⁶-5β-pregnene of melting point 175°-176°C. [α]_(D) = -1° (0.65). IR:3,520, 3,400, 1,725 and 1,250.

EXAMPLE 9 260 mg of(20R)-3β-methoxy-3α,9α-oxido-11α,20-diacetoxy-14.beta.,18-dihydroxy-Δ¹⁶-5β-pregnene are dissolved in 6 ml of absolute dimethylsulphoxide, 6 mlof absolute acetic anhydride are added and the mixture is left to standfor 17 hours at room temperature. It is then worked-up and the resultingcrude product is chromatographed in a benzene-ethyl acetate (4:1)mixture. This yields 220 mg of(20R)-3β-methoxy-3α,9α-oxido-11α,20-diacetoxy-14.beta.-methyl-thiomethoxy-18-oxo-Δ¹⁶-5β-pregnene in the amorphous form. IR: 2,750, 1,735 and 1,245. EXAMPLE10 298 mg of(20S)-3β-methoxy-3α,9α-oxido-11α,20-diacetoxy-14.beta.,18-dihydroxy-Δ¹⁶-5β-pregnene are reacted in 9 ml of dimethylsulphoxide-acetic anhydride(1:1) mixture, as in the preceding example, and the product is thenworked-up and chromatographed in benzene-ethyl acetate (2:1) solution.This yields 255 mg of crystals of(20S)-3β-methoxy-3α,9α-oxido-11α,20-diacetoxy-14.beta.-methyl-thiomethoxy-18-oxo-Δ¹⁶-5β-pregnene of melting point 114°-115°C. [α]_(D) = + 24 (0.75), IR:2,830, 2,740, 1,735 and 1,245. EXAMPLE 11

120 mg of3β-methoxy-3α,9α-oxido-7α,11α-diacetoxy-14.beta.,18-dihydroxy-20-oxo-Δ¹⁶-5β-pregnene and 3 mg of p-toluenesulphonic acid in 3 ml of2,2-dimethoxypropane are stirred for 10 minutes at room temperature. Themixture is then added to aqueous NaHCO₃ solution, the whole is extractedwith ethyl acetate and the extract is washed with saturated aqueous NaClsolution until neutral. The crude product obtained after drying andevaporation of the organic phase is chromatographed, in benzene-ethylacetate (1:1) solution, on silica gel. This yields 100 mg of crystals ofthe (14 → 18)-acetonide of3β-methoxy-3α,9α-oxido-7α,11α-diacetoxy-14.beta.,18-dihydroxy-20-oxo-Δ¹⁶-5β-pregnene (melting point 194°-195°C after one recrystallisation).[α]_(D) = - 65° (0.60), IR: 1,730, 1,665, 1,620 and 1,240. UV: 236(9,580).

EXAMPLE 12

40 mg of the (14 → 18)-acetonide of3β-methoxy-3α,9α-oxido-7α,11α-diacetoxy-14.beta.,18-dihydroxy-20-oxo-Δ¹⁶-5β-pregnene, in 3 ml of absolute dioxane, are reduced with 160 mg ofLi[Al(t-amyloxy)₃ H] for 15 minutes at 80°C. The mixture is then addedto saturated aqueous (NH₄)₂ SO₄ solution, the whole is extracted withethyl acetate and the extract is subsequently washed with saturatedaqueous NaCl solution until neutral. After drying and evaporation of theorganic phase, 40 mg of crude product result, and are chromatographed,in methylene chloride-methanol (100:1) solution, on silica gel. First,23 mg of (14 → 18 )-acetonide of(20R)-3β-methoxy-3α,9α-oxido-7α,11α-diacetoxy-14β,18,20-trihydroxy-Δ¹⁶-5β-pregnene are eluted, melting at 206- 207°C after onecrystallisation. [α]_(D) = - 33° (0.45). IR: 3,460 (broad), 1,730 and1,240.

Later fractions yield 7 mg of (14 → 18)-acetonide of(20S)-3β-methoxy-3α,9α-oxido-7α,11α-diacetoxy-14β,18,20 -trihydroxy-Δ¹⁶-5β-pregnene, melting at 160°-161°C after crystallisation. [α]_(D) = -36° (0.50). IR: 3,590, 3,450 (broad), 1,730 and 1,240.

200 mg of the starting material used, in 15 ml of absolute methanol, aretreated with 200 mg of solid NaBH₄ at -30°C. The mixture is then left at-30°C for 24 hours whilst stirring, a further 100 mg of NaBH₄ beingadded after 5 hours. The whole is then diluted with ethyl acetate andwashed with saturated aqueous NaCl solution until neutral. After dryingand evaporation of the organic phase, the residue is chromatographed asabove. First, 50 mg of the (20R) compound described above are eluted.Later fractions yield 120 mg of the (20S) compound described above.

EXAMPLE 13

120 mg of (14 → 18)-acetonide of(20S)-3β-methoxy-3α,9α-oxido-7α,11α-diacetoxy-14β,18,20-trihydroxyΔ¹⁶-5β-pregnene are acetylated in 5 ml of acetic anhydridepyridine (1:1)mixture for 3 hours at room temperature. The mixture is then evaporatedin vacuo, which yields 125 mg of (14 → 18)-acetonide of(20S)-3β-methoxy-3α,9α-oxido-7α,11α,20-triacetoxy-14β,18-dihydroxy-.DELTA.¹⁶ -5β-pregnene(IR: 1,730 and 1,240), which are reacted, without purification, in 6 mlof absolute methanol with a solution of 6 mg of p-toluenesulphonic acidin a further 6 ml of absolute methanol for 15 minutes at roomtemperature. The mixture is then diluted with ethyl acetate, washed withsaturated aqueous NaCl solution until neutral and evaporated in vacuoand the crude product (115 mg) is crystallised from etherhexane.(20S)-3β-Methoxy-3α,9α-oxido-7α,11α,20-triacetoxy-14β,18-dihydroxy-Δ¹⁶-5β-pregnene of melting point 172°-173°C is thus obtained. [α]_(D) = +48° (0.35), IR: 3,580, 3,460 (broad), 1,730 and 1,240.

EXAMPLE 14

160 mg of (20S)-3β-methoxy-3α,9α-oxido-7α,11α,20-triacetoxy-14β,18-dihydroxy-Δ¹⁶ -5β-pregnene are dissolved in 3ml of absolute dimethylsulphoxide, 3 ml of absolute acetic anhydride areadded and the mixture is left overnight at room temperature. It is thenadded to ice-cold aqueous NaHCO₃ solution, the whole is extracted withethyl acetate and the extract is washed with a large amount of wateruntil neutral. The crude product obtained after drying and evaporationof the organic phase is chromatographed, in benzene-ethyl acetate (3:1)solution, on silica gel. This yields 130 mg of crystals of(20S)-3β-methoxy-3α,9α-oxido-7α,11α,20-triacetoxy-14β,0-methyl-thiomethoxy-18-oxo-Δ¹⁶-5β-pregnene, melting at 125°-126°C after crystallisation. [α]_(D) = +25° (0.40). IR: 2,740, 1,730 and 1,240.

EXAMPLE 15

The starting substance of Example 11 can be obtained as follows:

720 mg of3β-methoxy-3α,9α-oxido-7α-hydroxy-11α,18-diacetoxy-20-oxo-5β-pregnane[Helv. 54. 2,879 (1971)] are acetylated in 30 ml of aceticanhydride-pyridine (1:1) mixture under a N₂ atmosphere for 6 hours at130°C. The reaction mixture is then evaporated in vacuo and the residue,in ethyl acetate-chloroform (1:1) solution, is chromatographed on silicagel. This yields 470 mg of3β-methoxy-3α,9α-oxido-7α,11α,18-triacetoxy-20-oxo-5β-pregnane, whichafter one recrystallisation melt at 146°-147°C. [α]_(D) = + 81° (0.64).IR: 1,735, 1,710 and 1,245.

470 mg of 3β-methoxy-3α,9α-oxido-7α,11α,18-triacetoxy-20-oxo-5β-pregnanein 40 ml of CCl₄ are boiled with 200 mg of N-bromosuccinimide, withaddition of 10 mg of azobisisobutyronitrile, for 45 minutes whilstirradiating externally with a 1000 W incandescent lamp. The succinimidewhich has precipitated is then filtered off and the filtrate isevaporated in vacuo. The resulting crude bromination product isdissolved in 40 ml of absolute dimethylformamide and warmed, with 470 mgof LiBr and 470 mg of Li₂ CO₃, to 130°C over the course of 21/2 hours,under N₂. The mixture is then concentrated in vacuo, diluted with ethylacetate and repeatedly washed with water. The crude product resultingafter drying and evaporation of the organic phase is chromatographed, inethyl acetate-chloroform (1:1) mixture, on silica gel. This yields 265mg of crystals of 3β-methoxy-3α,9α-oxido-7α,11α,18-triacetoxy-20-oxo-Δ¹⁶-5β-pregnene, which after one recrystallisation melt at 187°-188°C.[α]_(D) = + 53° (0.54). IR: 1,730, 1,670, 1,595, and 1,240; UV. 235(8,550).

265 mg of the product thus obtained and 110 mg of N-bromosuccinimide aswell as 10 mg of azobisisobutyronitrile, in 40ml of CCl₄, are boiled for20 minutes under external irradiation from a 1,000 W incandescent lamp.The mixture is then cooled, freed of the precipitated succinimide byfiltration, and evaporated in vacuo. The crude bromination product iswarmed under N₂ with 265 mg of LiBr and 265 mg of Li₂ CO₃ in 20 ml ofabsolute dimethylformamide to 130°C for 15 minutes. The mixture is thenevaporated in vacuo, the residue is taken up in ethyl acetate and thesolution is repeatedly washed with water. The crude product which isobtained after evaporation in vacuo is chromatographed, in benzene-ethylacetate (1:1) solution, on silica gel. This yields 185 mg of crystals of3β-methoxy-3α,9α-oxido-7α,11α,18-triacetoxy-20-oxo-Δ¹⁴,16-5β-pregnadiene, which after one recrystallisation melt at 209°C. [α]_(D) = + 227° (0.60). IR: 1,735, 1,640, 1,530, 1,465 and 1,240. UV:309 (10,900).

187 g of the product thus obtained, in 18 ml of CHCl₃ -methanol (100:1)mixture, are epoxidised with 185 mg of p-nitroperbenzoic acid for 24hours at room temperature, in the dark. The mixture is then diluted withethyl acetate and is washed successively with aqueous solutions ofNaI,Na₂ S₂ O₃,NaCl, NaHCO₃ and again NaCl. It is then dried over MgSO₄and evaporated in vacuo and the residue, in ethyl acetate-chloroform(1:1) solution, is chromatographed on silica gel. 109 mg of crystals of3β-methoxy-3α,9α;14β,15β-dioxido-7α,11.alpha.,18-triacetoxy-20-oxo-Δ¹⁶-5β-pregnene are eluted, melting at 199°-200°C after onerecrystallisation. [α]_(D) = + 33° (0.65). IR: 1,735, 1,670, 1,605 and1,250. UV: 244 (7,850).

250 mg of the product thus obtained in a mixture of 28 ml of methanoland 2 ml of cyclohexene are boiled, in the presence of 375 mg of 5 percent strength Pd-BaSO₄ catalyst, for 3 hours with vigorous stirring, atan oil bath temperature of 120°C. The catalyst is then removed byfiltration through Celite, the filtrate is evaporated in vacuo and theresidue, in a benzene-methanol (40:1) mixture, is chromatographed onsilica gel. This yields 155 mg of3β-methoxy-3α,9α-oxido-7α,11α,18-triacetoxy-14β-hydroxy-20-oxo-Δ¹⁶-5β-pregnene in the amorphous form. IR: 3,580, 1,735, 1,670, 1,615 and1,250. UV: 836 (9,860).

205 mg of the product thus obtained, in 20 ml of 0.1 N NaHCO₃ in 90 percent strength aqueous methanol, are boiled for 15 minutes under N₂ (oilbath temperature 80°C). The mixture is then diluted with ethyl acetate,washed with saturated aqueous NaCl solution until neutral and evaporatedin vacuo, and the residue, in ethyl acetate, is chromatographed onsilica gel. This yields 140 mg of crystals of3β-methoxy-3α,9α-oxido-7α,11α-diacetoxy-14.beta.,18-dihydroxy-20-oxo-Δ¹⁶-5β-pregnene, which melt at 222°C after two crystallisations. [α]_(D)= - 41° (0.50). IR: 3,600, 3,450, 1,730, 1,655, 1,610 and 1,240. UV: 236(9,960).

EXAMPLE 16

The conversion of the product obtained in Example 14 intobatrachotoxinin A is carried out as follows:

220 mg of(20S)-3β-methoxy-3α,9α-oxido-7α,11α,20-triacetoxy-14β-methyl-thiomethoxy-18-oxo-Δ¹⁶-5β-pregnene are dissolved in 4 ml of absolute benzene and warmed,together with 1.5 ml of a saturated solution of methylamine in benzene,for 9 hours to 85°C in a bomb tube. The mixture is then cooled andevaporated in vacuo. This yields 220 mg of(20S)-3β-methoxy-3α,9α-oxido-7α,11α,20-triacetoxy-14β-methyl-thiomethoxy-18methylimino-Δ¹⁶-5β-pregnene (IR: 2,770, 1,730, 1,665 and 1,240), which are reduced,without purification, in 18 ml of methanol, at room temperature, with220 mg of NaBH₄ in 2 ml of water, over the course of 10 minutes. Themixture is then diluted with ethyl acetate, washed with saturatedaqueous NaCl solution until neutral, dried over MgSO₄ and evaporated invacuo. This yields 210 mg of (20S)-3β-methoxy-3α,9α-oxido-7α,11α,20-triacetoxy-14β0-methyl-thiomethoxy-18-methylamino-Δ¹⁶-5β-pregnene (IR: 3,340, 2,800, 1,730 and 1,240), which are againtreated successively, without purification, in 20 ml of alcohol-freechloroform, at 0°C, with 1.5 ml of chloroacetyl chloride and 0.28 g ofNaOH in 20 ml of water. The two-phase system is then left for 15 minutesat 0°C whilst stirring vigorously and is subsequently poured ontosaturated aqueous NaHCO₃ solution, the mixture is extracted with ethylacetate and the extract is washed with saturated aqueous NaCl solutionuntil it is neutral. After drying and subsequent evaporation of theorganic phase, 220 mg of(20S)-3β-methoxy-3α,9α-oxido-7α,11α,20-triacetoxy-14β-methyl-thiomethoxy-18-(N-methyl-N-chloroacetyl-amino)-Δ¹⁶-5β-pregnene are obtained, which are left, without prior purificationand characterisation, for 13/4 hours at room temperature in 10 ml of an0.05 N HCl solution in absolute methanol. This mixture is then pouredinto aqueous NaHCO₃ solution, the mixture is extracted with ethylacetate and the extract is washed with saturated aqueous NaCl solutionuntil neutral. The crude product obtained after drying and evaporationof the organic phase is subsequently chromatographed, in benzene-ethylacetate (1:1) solution on silica gel. This yields 150 mg of crystals of(20S)-3β-methoxy-3α,9α-oxido-7α,11α,20-triacetoxy-14β-hydroxy-18-(N-methyl-N-chloroacetyl-amino)-Δ¹⁶-5β-pregnene, the melting point of which after one crystallisation is203°-204°C. [ α]_(D) = + 39° (0.40). IR: 3,350 (broad), 1,730, 1,645 and1,245.

170 mg of NaH dispersion are freed of adhering mineral oil by washingfour times with absolute pentane. The material is then covered with 5 mlof absolute benzene and 80 mg of(20S)-3β-methoxy-3α,9α-oxido-7α,11α,20-triacetoxy-14β-hydroxy-18-(N-methyl-N-chloroacetyl-amino)-Δ¹⁶-5β-pregnene in 5 ml of absolute tetrahydrofurane are added under argon.Finally, one drop of a solution of 20 mg of ethanol in 10 ml of absolutebenzene is also added and the mixture is boiled under argon, and whilststirring, for 2 hours. 0.4 ml of methanol is then added and the mixtureis boiled for a further hour in order to hydrolyse the acetate groupingson C-7, C-11 and C-20. It is then poured onto saturated aqueous (NH₄)₂SO₄ solution, the mixture is extracted with ethyl acetate, and theorganic phase is washed with saturated aqueous NaCl solution untilneutral, dried and evaporated in vacuo. This yields 50 mg of crude(20S)-3β-methoxy-3α,9α-oxido-7α,11α,20-trihydroxy-14β0,18N-[ep(oxy-2'-oxo-ethano)-N-methylimino)]-Δ¹⁶ -5β-pregnene (IR: 3,500(broad) and 1,635), which are acetylated, without purification, in 4 mlof acetic anhydride-pyridine (1:1) mixture overnight at roomtemperature. The whole is then evaporated in vacuo and the residue ischromatographed in ethyl acetate-methanol (9:1) solution. This yields 47mg of crystals of(20S)-3β-methoxy-3α,9α-oxido-7α-hydroxy-11α,20-diacetoxy-14β0, 18N-[ep(oxy-(2'-oxoethano)-N-methylimino)]-Δ¹⁶ -5β-pregnene, which melt at254°-255°C after one crystallisation. [α]_(D) = + 114° (0.40). IR:3,510, 2,860, 2,840, 1,730, 1,635 and 1,240.

30 mg of the product thus obtained, in 0.9 ml of absolute pyridine and0.02 ml of SOCl₂, are left for 2 hours at room temperature. The mixtureis then poured into aqueous NaHCO₃ solution and extracted with ethylacetate, and the extract is washed with saturated aqueous NaCl solutionuntil neutral. The crude product which arises after drying andevaporation of the organic phase is purified by means of preparativethin layer chromatography, in ethyl acetate as the migrating agentsystem. This yields 15 mg of (20S)-3β-methoxy-3α, 9α-oxido-11α,20-diacetoxy-14β O, 18N-ep[(oxy-(2'-oxo-ethano)-N-methylimino)]-Δ⁷,16-5β-pregnadiene in the amorphous form, which according to thin layerchromatography is a single substance. IR: 2,840, 1,730, 1,650 and 1,635(double band) and 1,250.

19 mg of this product in 3 ml of absolute ether are boiled for 5 hourswith 40 mg of LiAlH₄. The excess hydride is then destroyed by carefullyadding saturated aqueous (NH₄)₂ SO₄ solution and the mixture issubsequently poured into 5 per cent strength aqueous NH₃ solution. It isthen extracted with ethyl acetate and the organic phase is washed withsaturated aqueous NaCl solution until neutral, dried and evaporated invacuo. The resulting crude product is purified by means of preparativethin layer chromatography in the systemcyclohexane-chloroform-triethylamine-methanol (16:4:1:1). This yields 10mg of (20S)-3β-methoxy-3α,9α -oxido-11α,20 -dihydroxy-14β O,18N-[epoxyethano-N-methylimino)]-Δ⁷,16 -5β-pregnadiene, which is asingle substance, in the amorphous form. IR: 3,340, 2,840, 1,100 and990.

10 mg of this product in 1.5 ml of 90 per cent strength aqueous acetoneare boiled with 1.5 mg of p-toluenesulphonic acid for 1 hour. Themixture is then added to dilute aqueous 5 per cent strength NH₃ solutionand extracted with ethyl acetate, and the extract is washed withsaturated aqueous NaCl solution until neutral. The crude batrachotoxininA resulting after drying and evaporation of the organic phase ispreparatively purified on thin layer plates in the systemcyclohexane-chloroform-triethylamine-methanol (16:4:1:1). This yields 5mg of batrachotoxinin A in the amorphous form, which proves identicalwith natural batrachotoxinin A according to a thin layer chromatogram inthe systems cyclohexane-chloroform-triethylamine-methanol (16:4:1:1 or16:4:1:2) and ethyl acetate-methanol (4:1) and according to the IRspectrum, mass spectrum and NMR spectrum.

The NMR spectrum of natural batrachotoxinin A published by Witkop(Journal of the American Chemical Society 91, 3,931 (1969)) is thespectrum of the corresponding deuterochloride which has been produced,prior to the NMR recording, in deuterochloroform contaminated bydeuterohydrochloric acid. Apart from this, various signal allocationsadditionally had to be changed. The NMR values for synthetic and naturalbatrachotoxinin A are: NMR.: 0.88/s CH₃ -19, 1.40/d/J = 7 CH₃ -21,2.30-2.80/div. bm CH₂ = 2', 2.32 + 3.21/2d/J₁₅,15 = 19 (additional finestructure due to J₁₅,16 = 3 or 2) CH₂ = 15 (on irradiation with thefrequency of the olefine proton CH-16 the two additionally resolveddoublets are simplified to two doublets with J₁₅,15 = 19). 2.35/s NCH₃,2.71/s CH₂ -18, 3.78/d/J₁₁,12.sub.α = 9 (additional fine structure dueto J₁₁,12.sub.β = 4), CH-11, 3.55 + 4.05/2m CH₂ -1', 4.46/q/J = 7 CH-20(on irradiation with the frequency of CH₃ -21, the signal simplifies toa singlet), 5.66/m CH-16, 6.24/d/J₆.sub.β, 7 = 6 (additional finestructure due to J₆.sub.α, 7 = 2) CH-7 [CDCl₃ + D₂ O]. ]

MS (mass spectrum) M⁻ = 417 (3.5%), 330 (100%).

EXAMPLE 17

The conversion of the product obtained in Example 9 into3-0-methyl-7,8-dihydroepi-batrachotoxinin A can be carried out asfollows:

200 mg of (20R)-3β-methoxy-3β, 9β-oxido-11β, 20 diacetoxy-14-β -methylthiomethoxy-18-oxo-Δ16 -5β-pregnene in 4 ml of absolute benzene arewarmed with 2 ml of saturated methylamine solution in benzene for 7hours to 80°C in a bomb tube. The mixture is then cooled and evaporatedin vacuo. The resulting 205 mg of the crude Schiff's base of thealdehyde employed, in 15 ml of methanol, are reduced with 200 mg ofsodium borohydride in 1 ml of water for 10 minutes at 15°C. The mixtureis then worked up and the resulting amine (200 mg) is dissolved in 20 mlof alcohol-free chloroform. 1.5 ml of chloroacetyl chloride and 140 mgof sodium hydroxide in 20 ml of water are added to this solution at 0°C,with vigorous stirring. After 15 minutes the mixture is worked up. Thisyields 250 mg of crude 3β-methoxy-3α, 9α-oxido-11α, 20-diacetoxy14β-methyl-thiomethoxy-18-(N-methyl-N-chloroacetyl-amino)-Δ¹⁶ -5β-pregnene,which is again left, without purification, for 2 hours at roomtemperature in 20 ml of 0.05 N absolute HCl in methanol. Working upagain, and chromatography in benzeneethyl acetate (1:1) solution,finally yields 80 mg of crystalline (20R)-3β-methoxy-3α,9α-oxido-11α,20-diacetoxy-14β-hydroxy-18-(N-methyl-N-chloroacetyl-amino)-Δ.sup.16-5β-pregnene, which after purification by crystallisation has a meltingpoint of 176°-178°C, optical rotation [α]_(D) = +35° (0.29) and IR bands3,350 (broad), 1,725, 1,640 and 1,245, and which is identical with thecompound described in Helvetica Chimica Acta 54, page 2,793 (1971) andreferred to as 3β-methoxy-3α, 9α-oxido-11α,20ξ-diacetoxy-14β-hydroxy-18-(N-methyl-N-chloroacetyl-amino)-.DELTA.¹⁶-5β-pregnene.

The conversion of this product, according to the instructions in Helv.Chimica Acta, loc. cit., into the compound described there as3-0-methyl-20ξ-7,8-dihydrobatrachotoxinin yields the 20R-epimer of3-0-methyl-7,8 dihydroepi-batrachotoxinin A, from which7,8-dihydro-epibatrachotoxinin A is obtained by saponification of theetherified hydroxyl group in the 3-position in a manner which is initself known.

EXAMPLE 18

The conversion of the product obtained according to Example 10 into7,8-dihydrobatrachotoxinin A can be carried out as follows:

(20S)-3β-Methoxy-3α,9α-oxido-11α,20-diacetoxy-14.beta.methyl-thiomethoxy-18-oxo-Δ¹⁶-5β-pregnene is converted according to the instructions reproduced inthe preceding example into(20S)-3β-methoxy-3α,9α-oxido-11α,20-diacetoxy-14.beta.-hydroxy-18-(N-methyl-N-chloroacetyl-amino)-Δ¹⁶-5β-pregnene), 213 mg of this amorphous compound being obtained bychromatography in benzene-ethyl acetate (1:1) solution. IR: 3,450(broad), 1,725, 1,645 and 1,250.

320 mg of NaH dispersion are freed of the adhering mineral oil bywashing four times with absolute pentane. The product is then coveredwith 10 ml of absolute benzene and 228 mg of the above chloroacetate in10 ml of absolute tetrahydrofurane are added under argon. Finally, onedrop of a solution of 20 mg of ethanol in 10 ml of absolute benzene isalso added and the mixture is boiled under argon, and whilst stirring,for 6 hours. It is then cooled to 0°C and the excess hydride iscarefully decomposed with saturated aqueous (NH₄)₂ SO₄ solution.Customary working up and chromatography in ethyl acetate finally yield156 mg of crystals of(20S)-3β-methoxy-3α,9α-oxido-11α,20-diacetoxy-14.beta.0,18N-[ep(oxy-(2'-oxo ethano)-N-methylimino)]-Δ¹⁶ -5β-pregnene. Meltingpoint after crystallisation 166°-168°C. [α]_(D) = + 12° (1.14). IR:1,730, 1,634 and 1,250.

40 mg of the resulting compound are now reduced for 5 hours with 100 mgof LiAlH₄ in 10 ml of boiling absolute ether. After destroying theexcess hydride by careful addition of saturated aqueous (NH₄)₂ SO₄solution, the mixture is added to 5 per cent strength aqueous NH₃solution and worked up in the usual manner. Preparative thin layerseparation in the system cyclohexane-chloroform-triethylaminemethanol(16:4:1:1) yields 30 mg of crystals of (20S)-3β-methoxy-3α,9α-oxido-11α,20 -dihydroxy-14β0, 18N-[ep(oxyethano-N-methylimino)]-Δ¹⁶-5β-pregnene. Melting point, after one crystallisation, 151°-152°C.[α]_(D) = +57° (0.33). IR: 3,600, 3,450 (broad), 2,810, 1,105, 1,000 and960.

36 mg of the compound thus obtained are boiled with 28 mg ofp-toluenesulphonic acid in a mixture of 7 ml of acetone and 0.7 ml ofwater for 1 hour. The mixture is then added to 5 per cent strengthaqueous NH₃ solution and worked up in the usual manner. Preparative thinlayer chromatography of the crude product in the systemcyclohexanechloroform-triethylamine-methanol (16:4:1:3) yields 31 mg ofcrystals of (20S)-3β-hydroxy-3α,9α-oxido-11α,20-dihydroxy-14β0,18N-[ep(oxyethano-N-methylimino)]-Δ¹⁶ -5β-pregnene (=7,8-dihydrobatrachotoxinin A) which when recrystallised once melt at169°-170°C. [α]_(D) = +57° (0.64), IR: 3,580, 3,400 (broad) 2,810,1,100, 1,080, 1,065, 1,030, 1,010, 1,000, 960, 925 and 855.

What we claim is:
 1. Process for the manufacture of 20-epimeric Δ¹⁶-steroid-14β, 18,20-triols of the formula ##SPC6##in which formula Prepresents the 17-pregnane side chain which has one of the two followingpartial formulae ##EQU7## wherein R represents a free, esterified oretherified hydroxyl group, X an etherified or esterified hydroxyl group,Y an esterified hydroxyl group, and Z denotes a hydrogen atom or anesterified hydroxyl group, the ester groups being derived fromcarboxylic acids having up to 18 carbon atoms and the etherifiedhydroxyl groups being derived from alcohols having up to 8 carbon atoms,characterised in that a corresponding Δ¹⁶ -20-oxosteroid-14β, 18-diol ofthe pregnane series in which the 14,18-diol grouping is ketalized with aketone of the formula ##EQU8## wherein W₁ and W₂ denote two loweraliphatic hydrocarbon radicals with 1-6 C-atoms or denote, together withthe carbon atom to which they are bonded, an alicyclic hydrocarbonradical with 5-12 carbon atoms and 5-7 ring carbon atoms, is treatedwith a complex light metal hydride which reduces an oxo group to ahydroxyl group but which leaves esterified hydroxyl groups intact, amixture of the 20(S)- and 20(R)- hydroxy compounds being formed, inwhich the ketalized 14,18-diol grouping is split subsequently by an acidtreatment to give the free 14,18-diol grouping.
 2. Process as claimed inclaim 1, wherein an alkali metal boron hydride is used as the complexlight metal hydride.
 3. Process according to claim 2, wherein thereaction is carried out at temperatures between -50° and 0°.
 4. Processaccording to claim 1, characterised in that a complex alkalimetal-aluminium hydride of the type ##EQU9## wherein X₁, X₂ and X₃ eachdenote a tertiary lower alkyl group and Me denotes an alkali metal, isused.
 5. Process according to claim 4 wherein the reduction is carriedout at temperatures between 0° and 100°.
 6. Process according to claim1, wherein any of the 20-epimeric alcohols obtained is esterified priorto the liberation of the 14,18-diol grouping from the ketalized form. 7.Process according to claim 6, wherein the resulting 20-ester of a14β,18,20-triol is treated, after having protected any other freehydroxyl groups present, with a sulphoxide of one of the formulae##EQU10## in which formulae V₁ -V₅ denote hydrogen or lower alkyl groupsor phenyl-lower alkyl groups and 0 denotes a phenyl nucleus, and a loweraliphatic carboxylic acid anhydride in order to dehydrogenate the18-hydroxyl group to the aldehydo group and to etherify, simultaneously,the 14β-hydroxyl group with a residue of a 2-thiapropanol or a2-thiaarylethanol, corresponding to the sulphoxide used, and having oneof the formulae ##EQU11## wherein V₁ -V₅ have the meaning given above.8. Process as claimed in claim 1, wherein a mixture of dimethylsulfoxideand acetic anhydride is used as the reagent.
 9. A compound of theformula ##SPC7##in which P represents a side chain of one of the twofollowing partial formulae ##EQU12## wherein R represents a freehydroxyl group or a hydroxyl group esterified with a lower aliphaticcarboxylic acid, A represents a hydroxyl group together with a hydrogenatom or an oxo group, X represents a hydroxyl group etherified with alower aliphatic alcohol with 1-5 C-atoms or esterified with a loweraliphatic carboxylic acid, Y a hydroxyl group esterified with a loweraliphatic carboxylic acid and Z a hydrogen atom or a hydroxyl groupesterified with a lower aliphatic carboxylic acid, whereby in compounds,in which A represents the oxo group, the 14β-hydroxyl group isetherified with a 2-thiapropanol of the formula ##EQU13## in which V₁-V₅ denote hydrogen or lower alkyl, and which has up to 8 C-atoms.
 10. Acompound as claimed in claim 9 which is selected from the groupconsisting of the 20R-3β-methoxy-3α,9α-oxido11α,20-diacetoxy-14β,18-dihydroxy-Δ¹⁶-5β-pregnene, 20 S-3βmethoxy-3α,9α-oxido-11α,20-diacetoxy-14β,18-dihydroxy-Δ¹⁶ 5β-pregnene, thecorresponding 18-oxo compounds, and the 14-ether of same derived from2-thiapropanol.
 11. A compound as claimed in claim 9 and which is amember selected from the group consisting of the 20S-3β-methoxy-3α,9α-oxido-7α, 11α, 20-triacetoxy-14β,18-dihydroxy-Δ¹⁶-5β-pregnene, the corresponding 18-oxo-derivative, and the 14-ether ofsame derived from 2-thiapropanol.